16-methyl-15-dehydro-corticoids



United States Patent 30 Claims. (61. 260-39745) The present invention relates 'to new cyclopentanophenanthrene derivatives.

More specifically, it relates to novel steroidal A -cortical hormones of the formula:

CHzOR LQIQ and =0; X is selected from the group consisting of hydrogen and fluorine, and Z represents the linkage between C-l and 0-2 selected from the group consisting of single bond and double bond.

The hydrocarbon carboxylic acid from which the aforesaid acyl radical is derived is either saturated or unsaturated, of straight, branched, cyclic or mixed straight (branched)-cyclic chain, which acid may be substituted with group such as hydroxyl, O-acyl (of less than 12 carbon atoms), alkoxy (of less than 9 carbon atoms), amino or halogen (fluorine, chlorine or bromine); typical esters among the novel compounds are the acetate, pr-opionate, i-butyrate, hemisuccinate, enanthate, caproate, benzoate, trimethylacetate, phenoxyacetate, aminoacetate and ,8- chloropropionate.

- The acyl groups may further derive from sulf-onic acids or from sulfuric acid; the new compounds can also'be under the form of derivatives soluble in water, such as for example the alkali salts of their hernisuccinates, the disodium salts of their esters formed with phosphoric acids, or the hydrohal-ides of esters formed with aminoacids.

The above described new compounds are hormones of cortical activity and are particularly active as anti-estrogenic and glycogenic agents. The 17,2l-diesters of these compounds are progestational agents.

The new compounds possess as functional groups apart from the necessary 3-keto-A -arrangement, an oxygen function at C-1 1, a free or esterified hydroxyl group at 0-21, a free or esterified hydroxyl group at C-17a and optionally a halogen atom at C-9u.

"ice

rangement of a double bond between 0-4 and C- and introduction of a double .bond between C-1 and C-2 can be carried out without affecting the double bond at C-15. The process of producing the above described novel 5 compounds comprises, for instance, reacting a compound of the general formula wherein X, Y and Z have the above explained meaning, with iodine in the presence of .an inert organic nor-ketonic solvent including a minor proportion of a lower aliphatic alcohol and a compound selected from the group consisting of oxides, salts and hydroxides of the alkali-metals and alkaline earth metals and reacting the resulting 21-iodocompound with anhydrous potassium acetate so as to obtain the corresponding 21-acetoxy derivative, reacting the latter with chromic acid, and then with potassium hydroxide, so as to obtain the corresponding A -3-ketone.

This process further com-prises the other reactions enumerated hereinbefore, and is correspondingly illustrated, although by way of example only, in the following Reaction Diagram 1:

REACTION DIAGRAM I i J-c H, {\fj/ r (H v) CHQOR CHzOR Ref-j an 0=l 15 1 2113 a a on o 0: (v) (v1) The starting materials utilized in this process of which the compound I in the above Reaction Diagram I, namely 16 methyl A pregnadiene 3fl,17a diol 20 one, is representative, are produced by a process illustrated in the following reaction equation:

and comprising reacting a l6/3-methyl-16a,l7a-oxido-20- keto-pregnane derivative (A) with a hydrogen halide, preferably aqueous concentrated hydrobromic acid, in an inert organic solvent, preferably acetone at a temperature in the range from -10 C. and lower to room temperature preferably between 0 and +10 C.

We assume that during the above described treatment with the hydrogen halide, there is formed an intermediate 16-methyl- 16,17-bromohydrin which spontaneously dehydrobrominates to yield the above unsaturated compound (B), i.e., the starting material for the process of the present invention as illustrated in Reaction Diagram I above.

The latter new process comprises, in random sequence, the monoiodination of the starting compound (I), or an analog compound having the same grouping B above, to obtain the corresponding 21-iodo derivative; the latter is acetolyzed to obtain the 21-acetoxy compound (II). The monoiodination and acetolysis were carried out preferably by the method described by Ringold, Stork et al. in Patent 2,874,154.

The hydroxyl group at C-3 was oxidized with chromic acid to the 3-keto group to produce a 16-methyl-21-ace- -t0xy-3-keto derivative such as compound (III); by alkaline treatment, the 2l-acetoxy group was hydrolyzed and a double bond present at 0-5 was simultaneously rearranged to produce the 16-methyl-l5-dehydro-analog of a 21-hydroxy-3-keto-A -pregnene such as compound (N); where the llfl-hydroxyl group was not present in the starting compound (I), it was introduced for instance by enzymatic treatment with bovine adrenal glands to obtain compound (V in which'R is preferably hydrogen, which was then'esterified to obtain the corresponding 21- esters or 17,21-dies'ters.

The 11 B-hydroxyl group of compound (V) was oxidized to the ll-keto group by reaction with chromic acid in aqueous acetic acid to yield compound (VI); the additional double bond at C-1,2 was introduced into compound V or VI by refluxing with selenium dioxide in mixture with t-butanol and in the presence of catalytic amounts of pyridine to obtain'the corresponding A -derivative (VII) or (VIII).

Where the starting material (I) was a compound satu rated in Ring A, the sequence of the above described reaction steps gave the S-allo dehydro and the S-normal dehydro analogs of compounds (V) and (VI); selenium dioxide treatment gave the corresponding l-dehydro derivatives, when applied to the 5-allo compounds, and the' A -dehydro derivatives when applied to the S-normalpregnan compounds.

Under stronger conditions, treatment of either 5-allo or S-normal pregnanes resulted in simultaneous introduction of two double bonds at C1,2 and (D-4,5.

Saponification by conventional methods yielded the free compounds corresponding to Formulas V, VI, VII and/or VIII.

The corresponding new 16-methyl-A cortical hormones fiuorinated at C-9d were obtained by treatment comprising the acetoxylation of 16-methyl-9a-fluor0-A -pregnene- 11B,17o-diol-3,20-dione (IX below) at C-21 via the 21- iodo intermediate, which method has been described above; the resulting 21-acetate of the respective l6-methyl- 9a -'fluoro A pregnene l1fi,17a,2l triol 3,20- dione (X below) was further dehydrogenated, for instance with selenium dioxide, to introduce either one new double bond between C-4 and C5, or simultaneously two new double bonds at C-4,5 and C-1,2; by hydrolysis of the acetoxy group at C-21 there were obtained the free alcohols and reesterification at C21 afiiorded the respec- REACTION DIAGRAM II CH CHz.O.CO.CH;

O C O H l (llHzOR CHzOR CO 30 to; to:

In this reaction diagram'R and Y have the meaning explained hereinbefore.

The starting material (IX) for these reactions was prepared by converting the known A -pregnen-3a-o1-1l, 20-dione to its 20-cycloethylene ketal, reducing the 11- keto to the llfl-hydroxy group, hydrolyzing the ketal group, reacting the resulting A -pregnene-3a,llfi-diol-ZO- one with diazomethane followed by pyrolysis of the resulting pyrazoline, aoetylating the '16-methyl-A -pregnene- 3a,1l,8-diol-20-one thus obtained at C-3, dehydrating the S-acetate with mesyl chloride in dimethylformamidepyridine, hydrolyzing the acetoxy group at C-3, and oxidizing the hydrolyzed product to l6-methyl-A pregnadiene-lZO-dione. The latter was treated by the method of Fried et al. for introducing a fluorine atom at C9a as described in J. Am. Chem. Soc. 79, 1130 (1957), to obtain the corresponding 16-methyl-9a-fluoro-A pre'gnen-1rlB-ol-3,ZO-dione, the Cl6,17 double bond of which was then epoxidized with hydrogen peroxide in alkaline conditions, and the resulting 1-6oc,17ot-OXid0 derivative was reacted with hydrobromic acid in acetone thus 3,257,434 6 affording the corresponding 16methyl-9a-flu 0ro-A Example 1 pregnene-l 1fl,17u-diol-3,20-dione (IX).

The production of the new compounds according to the invention is lfurthe-r illustrated, by way of example, by the preparation of 16-methyl-15-dehydno prednisone or 5 its esters from a different starting material by a process illustrated in Reaction Diagram III below:

To a mixture of 8 g. of l6methyl-A -pregnadiene- 3fl,17a-diol-20-0ne, 60 cc. of redistilled tetrahydrofura-ne and 36 cc. of methanol were added 12 g. of powdered calcium oxide and then 12 g. of iodine, with vigorous stirring and maintaining the temperature around REACTION DIAGRAM III CH; v (EH OCQCH ('30 --OH O:, CH;;

acetoxylation no- HO l (IA) l (IIA) H H loxidatlon onion omoooom o 0 (G i "lil O=\/ (VIII) 7 0* l (IIIA) H The treatment of the starting material 16-methyl-A of iodine disappeared. I lt. of methylene chloride was allopregnene-3B,17a-diol-l1,20-dione-3-acetate (IA) for added and the solid was removed by filtration; the filtrate obtaining 16-methyl-l5dehydro-prednisone or one of its was washed with 10% aqueous sodium thiosulfate soluesters (VIII) is identical with the steps described above in 40 tion and water, dried over anhydrous sodium sulfate and connection with Reaction Diagram I leading from comevaporated to dryness under reduced pressure and at room pound (lI) via compound (II) to compound (III) therein. temperature. The residue, consisting of the crude 16- Correspondingly, there are obtained in the present process methyl-21-iod oA -pregnadiene-3fl,l7a-diol-20-one, was first the ZI-acetates of 16-rnethyl-A allopregnene-3B,17umixed with 1 lt. of dry acetone and 20 g. of anhydrous 2l-triol-'11,20-dione (IIA) and then 16-methyl-A -allopotassium acetate, refluxed for 18 hours, concentrated |pregnene-17a,2l-diol-3,11,2Q-trione 2l-acetate (II'IA). to -a small volume, diluted with water and the precipitate The latter is then dehydnogenated with selenium dioxide formed was collected by filtration, washed with water, and eventually saponified and reesterified in a oonvendried and recrystallized from acetone-hexane, thus yieldtional manner to obtain com-pounds (VIII). ing the 2l-acetate of 16-.methyl-A Y -pregnadiene-3fi,17a,

Another group of new steroidal A -hormones accord- 2l-tri ol-20-one, M.P. 193-195 (3., [0:1 98 (chloroing to the invention are described by the formula below, form). in which R, X, Y, and Z have the same meaning as stated A solution of 5 g. of the above compound in 200 cc.

hereinbefore: of acetone was cooled to 0 C., flushed with nitrogen and treated with an 8 N solution of chromic acid, under CH2OR stirring at 0 C. and under an atmosphere of nitrogen,

00 7 until the color of chromium trioxide persisted in the mixture (the 8 N solution of chromic acid had been prepared Y a by dissolving 26.7 g. of chromium trioxide in 23 cc. of l J concentrated sulfuric acid and diluting with distilled wamore at 0 C. under an atmosphere of nitrogen, then diluted with ice water and the precipitate was collected, washed with water, dried and recrystallized from acetonehexane, to produce the 21-acetate'of l6-methyl-A -preg- These new A -trienes and A -tetraenes are also nadiene-lh'z1-di01'3,20-di0I1e- Z l 60 ter to 100 cc.). The mixture was stirred for 5 minutes hormones of cortical activity, and are especially anti- A mixture of 4 of the above compound and 200 androgenicagents. of 1% methanolic potassium hydroxide solution was These new compounds are obtained from the cone. stirred at 5 C. for 1 110111, acidified With acetic acid, sponding compounds selected from the first class of new concentrated to a Small Volume, diluted with Water and steroidal A -hormones V, VI, VII, VIII, XI and XII, the precipitate was collected, washed with water, dried described hereinbefore, by introduction 01f a further double and recrystallized from acetone-hexane, thllS aff rdi g 16- bond between 0-6 and 0-7 by dehydrogenation with methyl-A -pregnadiene 170:,21- diol-3,20-dione, M.P. chloranil. 2l2-2l5 C., A 240-242 m log 6 4.18.

The invention is further illustrated but not limite There were mixed 425 cc. of a 1.74% aqueous soluby the following examples: tion of dipotassium hydrogen phosphate (K HPO and C.; the stirring was continued at 25 C. until the color 75 cc. of a 1.38% aqueous solution of sodium dihydrogen phosphate (solution A). A mixture of 1 lt. of 4.5% aqueous sodium chloride solution, 40 cc. of 5.75% aqueous potassium chloride solution and 10 cc. of 19.1% aqueous magnesium sulfate solution was diluted to 5 lt. to form solution B. 20.9 g. of fumaric acid and 14.4 g. of sodium hydroxide were dissolved in 1 lt. of water .and diluted to 1.2 lt., to obtain solution C.

There were mixed 475 cc. of solution A, 4.32 lt. solution B and 1.2 lt. of solution C.

The fat was removed from the adrenal glands of recently slaughtered bovine and the glands were then ground in a meat grinder until an homogeneous mass was obtained; to 3 kg. of this mass was added 6 It. of the mixture of solutions A, B and C, stirring vigorously.

To the above mixture there was then added a solution of 3 g. of 16-methyl-A pregnadiene-l7a,2l-diol-3,2O- dione, in 16 cc. of propylene glycol, the mixture was stirred at 28 to 37 C. for 3 hours, and then 40 lt. of

acetone was added; the stirring was continued at room temperature for 1 hour further.

The solid was filtered, washed with 2 portions of 10 lt. of acetone, the washings were combined with the filtrate and the solution was concentrated to a volume of approximately 5 1t. under reduced pressure and taking care that the temperature did not rise over 30 C. The aqueous residue was washed with 3 portions of 4 lt. of hexane and the hexane was discarded. The washed aqueous residue was extracted with 2 portions of 3 lt. of methylene chloride and the extract was washed with water, dried over anhydrous sodium sulfate and concentrated to a volume of 300 cc. under reduced pressure and below room temperature. The concentrated solution was trans ferred to a column charged with a mixture of 90 g. of silica gel and 90 g. of celite, the column was washed with 3 lt. of methylene chloride and 10 cc. of acetone and finally with a mixture of 1600 cc. of methylene chloride and 400 cc. of acetone. The latter washing eluted the 16-methyl-1S-dehydro-hydrocortisone, which was purified by recrystallization from acetone-hexane.

A mixture of 2 g. of the above substance, 2 cc. of acetic anhydride and 10 cc. of pyridine was kept overnight at room temperature, then poured into water, heated on the steam bath for half an hour, cooled and the precipitate was collected, washed with water, dried and recrystallized from acetone hexane, thus furnishing the 21- acetate of 16-methyl-1S-dehydro-hydrocortisone.

A mixture of 1 g. of the above compound, 50 cc. of t-butanol, 300 mg. of selenium dioxide and a few drops of pyridine was refluxed for 48 hours under an atmosphere of nitrogen, diluted with ethyl acetate and filtered through celite. The solvent was removed by distillation under reduced pressure, the residue was triturated with water and the precipitate was collected, washed with water and purified by chromatography on neutral alumina, to produce the 21-acetate of l6-methyl-l5-dihydroprednisolone. 250 mg. of this substance was hydrolyzed to the free 16-methyl-15-dehydro-prednisolone by the reaction with methanolic potassium hydroxide described above.

A mixture of 500 mg. of the above acetate, 1 g. of chloranil, 12.5 cc. of ethyl acetate and 2.5 cc. of glacial acetic acid was refluxed under an atmosphere of nitrogen for 55 hours. The cooled mixture was washed with 5% aqueous sodium hydroxide solution until the washings were colorless, and then with water to neutral, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. By chromatography of the residue on neutral alumina, there was obtained the 21-acetate of 16-methyle-6,1S-bis-dehydro-prednisolone.

Alternatively, 5 00 mg. of the 21-acetate of 16-methyl- IS-dehydro-prednisolone, 25 cc. of t butanol and 500 mg. of chloranil were refluxed for 1 6 hours. The excess of chloranil was then filtered and the solution evaporated under vacuo. The residue was'dissolved in 300 cc. of ethyl acetate and the organic solution washed with 10% aqueous sodium hydroxide solution and water, as set lfOI'th above, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from methylene chloride-methanol, after decolorization with activated charcoal, gave also the ZI-acetate of 16-methyl- 6,15-bis-dehyd'ro-prednisolone.

The starting material, namely 1'6-methyl-A -pregnadime-3,8,l7a-diol-20-one was obtained in the following manner: a solution of 5 g. of 16-methyl-A -pregnadien-3/3-ol-20-one acetate described by Wettstein et al. in Helv. Chim. Acta XXVII, 1803 (1944), in 350 cc. of methanol was treated with 20 cc. of a 4 N aqueous solution of sodium hydroxide and immediately afterwards with 20 cc. of 30% hydrogen peroxide, with stirring and maintaining the temperature around 15 C. The mixture was kept overnight in the refrigerator, poured into ice water and the formed precipitate collected thus giving 16,8methyl-16a,l7a-oxido-A -pregnen- 3,B-o1 20-one.

A stirred solution of 2 g. of this epoxide in 160 cc. of acetone was treated with 8 cc. of an aqueous hydrobromic acid solution of constant boiling point, maintaining the temperature around 5 C. After 15 minutes the reaction mixture was poured into ice water, the precipitate was filtered and recrystallized from acetone hexane, to produce lfi-methyl-A -pregnadiene-3 8,17a-diol- 20-one.

Example 2 In accordance with the oxidation method described in Example 1, 5 g. of l6-methyl-A -pregnadiene-3B,17adiol-20-one was treated with an 8 N solution of chromic acid in acetone solution, to produce 16-methyl-A pregnadien-l7u-ol-3,20-dione. The latter compound was dissolved in cc. of glacial acetic acid, 5 cc. of concentrated hydrochloric acid were added and the reaction mixture was allowed to stand at room temperature for 4 hours. It was then poured into ice water, extracted with methylene chloride, the organic extracts were washed with 5% aqueous sodium carbonate solution and water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Chromatography of the residue on neutral alumina gave the pure l6-methy1-A pregnadien-l7oc-ol- 3,20-dione.

By treatment of the above compound with calcium oxide and iodine in mixture of tetrahydrofurane-methano], followed by acetoxylation of the 21-iodo derivative with potassium acetate in acetone solution, in accordance with the method described in Example 1, there was obtained the ll-acetate of 16-methyl-A -pregnadiene-l7a,21-diol-3,20-dione, M.P. l05ll0 C., solidifies and remelts at 155157, [ab +43 (chloroform), A 240 m log 6 4.19.

By following the method of Example 1, the above compound was saponified with 1% methanolic potassium hydroxide, thus affording l6-methyl-A -pregnadiene- 17a, 21-diol-3,20-dione, identical with that obtained in the previous example.

Incubation of the latter compound with adrenal glands, followed by acetylation, as described in Example 1, gave the 2ll-acetate of 16-methyl-15-dehydro-hydrocortisone.

A stirred solution of 5 g. of the above compound in 150 cc. of acetic acid was treated dropwise with a solution of 1.2 moles of chromium trioxide in 25 cc. of acetic acid, maintaining the temperature at 15-18" C.; the reaction mixture was kept at room temperature for 1 hour more, poured into ice water and the precipitate collected, washed with water to neutral, dried and recrystallized from acetone ether, ,thus affording the 2-1- acetate of 16-methyl-1S-dehydro-cortisone.

By following the dehydrogenation method of Example 9 IS-dehydro-prednisone, M.P. 191193 C., [ot] +128 (chloroform); h 236-238 mp, log 6 4.18.

Example 3 A solution of 3 g. of 16-methyl-1S-dehydro-hydrocon tisone, intermediate in the previous examples, in 15 cc. of pyridine, was treated with cc. of propionic anhydride and kept overnight at room temperature; it was then poured into water, heated for half an hour on the steam bath, cooled and the precipitate was collected, washed with water, dried and recrystallized from acetone hexane, thus alfording the 21-propionate of 16-methyl-15- dehydro-hydrocortisone.

By an analogous method to that described in the preceding example, there was then oxidized the 11,8-hydroxyl group to the keto group and the resulting 21-propionate of 16-methyl-1S-dehydro-cortisone was treated with selenium dioxide, in accordance with the method of Example 1 to produce the 21 propionate of 16-methyl-15-dehydro-prednisone, wherein there was then introduced a double bond at C-6,7 by the reaction with chloranil set forth above, thus furnishing the 21-propionate of 16- methyl-G,1S-bis-dehydro-prednisone. Hydrolysis of this compound with methanolic potassium hydroxide in accordance with the method described in Example 1, gave the free 16-methyl-6,15-bis-dehydro-prednisone.

Example 4 In accordance/with the method described in Example 1, 2 g. of the 21-a-cetate of 16-methyl-1S-dehydro-hydrocortisone, intermediate of the aforesaid example, was refluxed with chloranil in mixture with ethyl acetate and acetic acid; there was thus obtained the 21-acetate of 1'6-methyl-6,1S-bis-dehydro-hydrocortisone. Upon subsequent reaction with selenium dioxide under reflux, by following the procedure described also in Example 1, there was obtained the 21-a-cetate of 16-methyl-'6,15-bis-dehydro-prednisolone, identical with the compound mentioned in such example.

Example 5 A mixture of g. of A -pregnen-3ot-o1-11,20-dione, described by W. R. Nes et al. in J. Am. Chem. Soc. 73, 4765 (1951), 300 cc. of anhydrous benzene, 120 cc. of ethylene glycol distilled over sodium hydroxide and 1.6 g. of p-toluenesulfonic acid was refluxed for 12 hours with the use of a water separator. Aqueous sodium bicarbonate solution was added to the cooled mixture, the organic layer was separated, washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated. There was thusobtained the 20-cycloethyleneketal of A -pregnen-3a-ol-11,20-dione, which was used for the next step without further purification. A small amount was purified by chromatography on neutral alumina.

The above compound was dissolved-in 100 cc. of tetrahydrofurane and added to a mixture of 3 g. of lithium aluminum hydride and 200 cc. of anhydrous tetrahydrofurane, little by little, with stirring and cooling. The mixture was refluxed for 4 hours, cooled, treated dropwise with acetone to decompose the excess of hydride, then aqueous saturated sodium sulfate solution was added followed by anhydrous sodium sulfate; the solid was filtered and the solvent was evaporated from the filtrate; There was thus obtained 20-ethylenedioxy-A -pregnene- 304,1 1,8-diol in crude form. This compound was dissolved in 200 cc. of acetone, treated with 1 g. of p-toluenesulfonic acid and a few cc. of water and kept overnight at room temperature; it was then concentrated to a small volume under reduced pressure, diluted with water and the precipitate was collected, washed with water, dried and recrystallized from acetone-hexane, thus giving A -pregnene-3a,1lB-diol-20-one.

2 g. of the above compound were dissolved in 50 cc. of an ether solution of diazomethane prepared from 12.5 g. of nitrosomethylurea and the mixture was kept for 24 hours at room temperature. 1.2 cc. of acetic acid was then added, the solution was evaporated to dryness under reduced pressure in a bath at a temperature below 40 C. and the residue was recrystallized from acetoneto produce the pyrazoline, which was then decomposed by the thermal treatment described by Wettstein in Helv. Chim. Acta, XXVII, 1803 (1944), by gradually heating to 180 C. in high vacuum. Recrystallization from acetone of the crude product afforded 16-methyl-A -pregnene-3a,11,8- diol-20-one.

Treatment of the above compound with an excess of acetic anhydride in pyridine at room temperature, in a conventional manner gave the 3-acetate of 16-methyl- A -pregnene-3a,1 1,8-diol-20-one.

10 g. of the above compound were dissolved with slight heating in 125 cc. of dimethylformamide: the mixture was cooled, treated with 4.2 cc. of mesyl chloride and 5 cc. of pyridine and heated at C. for half an hour. Water was added to the cooled mixture, the product was extracted with ethyl acetate, the extract was washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated. Recrystallization of the residue from acetone-hexane yielded the acetate of 16-methyl- A -pregnadien-3u-ol-20-one.

8 g. of the above compound was treated with a solution of 5 g. of potassium hydroxide in a mixture of cc. of acetone and 20 cc. of water, heated on the steam bath for 1 hour, acidified with acetic acid, concentrated to a small volume under reduced pressure, diluted with water and the precipitate was collected, thus giving the free 16- methyl-A -pregnadien-3a-ol-20-one, which was used for the next step without further purification.

The above crude compound was dissolved in 200 cc. of acetic acid and slowly treated under stirring with a solution of 2 g. of chromium trioxide in 40 cc. of 50% acetic acid, taking care that the temperature remained below 15 C. It Was then stirred at this temperature for 1 hour more, poured into ice water and the precipitate was collected, washed with water, dried and recrystallized from acetone-hexane, thus affording 16-methyl-A pregnadiene-3,20-dione.

A mixture of 7.5 g. of the above compound, 75 cc. of pure dioxane and 12 cc. of 0.4 N perchloric acid was treated in the dark at room temperature with 4.2 g. of N- brornoacetamide which was added with stirring and in the course of 1 hour. The stirring was continued for 1 hour further and the solution was then treated with 10% sodium sulfite solution until the starch-potassium iodide indicator paper no longer turned blue; 500 g. of ice and cc. of chloroform were added and the organic layer was separated, successively washed with sodium bicarbonate solution and water, evaporated under reduced pressure in a bath at a temperaturebelow 25 C. and the residue was triturated with a little cold acetone. There was thus obtained 16-methyl-9a-bromo-A -pregnem11pol-3 ,20-dione.

The above crude compound was dissolved in 20 cc. of dioxane and slowly added to a mixture of 3.2 g. of anhydrous potassium acetate and 40 cc. of absolute ethanol which had been heated nearly to boiling. The mixture was refluxed for 45 minutes, cooled and treated with 50 cc. of ice water under continuous stirring. The precipitate was collected, washed with water and dried, thus yielding 16-methyl-9,8,11B-oxido-A -pregnene-3 ,ZO-dione.

The above crude product was dissolved in cc. of methylene chloride, cooled to 0 C. and the solution was treated with a mixture of 12 g. of anhydrous hydrogen fluoride and 20 cc. of tetrahydrofurane previously cooled in a Dry Ice-acetone bath; the hydrogen fluoride solution had been placed in a polyethylene flask fitted with a magnetic stirrer. The addition was effected little by little with stirring, over a period of about 20 minutes; the mixture was then stirred at 10 C. for 6 hours more, neutralized by the cautious addition of 5% aqueous sodium bicarbonate solution; the mixture was transferred to a separatory funnel and the organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated until abundant precipitation. After cooling, the precipitate was collected, redissolved in 40 cc. of hot ethyl acetate, filtered while hot from insoluble material and the filtrate was cooled, thus affording the crystalline 16-methyl-9ot-fluoro-A -pregnen-l 118-01-3,20-di0ne.

A solution of 5 g. of the above compound in 65 cc. of chloroform and 155 cc. of methanol was cooled to C. and treated under stirring with 10 cc. of 35 hydrogen peroxide and simultaneously with a solution of g. of sodium hydroxide in 50 cc. of water, dropwise and maintaining the temperature around 0 C. The mixture was then stirred for 1 hour more at 0 C., then at room temperature for 16 hours, poured into ice water, extracted with chloroform and the combined chloroform extracts were washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated. Recrystallization of the residue from acetone-hexane furnished 16-met-hyl- 90t-flllOIO-16OL,170L-OXldO-pICgHaI1-11,8-01-3 ,20-dione.

20 cc. of constant boiling aqueous hydrobromic acid solution was slowly added to a stirred solution of 5 g. of 16/3-methyl-9u-fluoro-16a,17a-oxido-pregnan 11,8 ol 3, 20-dione in 100 cc. of pure acetone, maintaining the temperature around C.; the mixture was stirred for 1 hour more at 10 C., diluted with ice water and the precipitate was collected, and recrystallized from acetone-hexane. There was thus obtained 16-methyl-9a-fluoro-A pregnene-l1B,17a-diol-3,20-dione.

In accordance with the method described in Example 1, the above product was then monoiodinated at C21 by reaction with iodine and calcium oxide in tetrahydrofurane-methanol, and the resulting 1.6-methyl-9u-fluoro- 21-iodo-A -pregnene-l1/3,17ot-diol-3,20-dione was treated with potassium acetate under reflux in mixture with acetone. There was thus produced the 21-acetate of 16-methyl-9a-fluoro-A -pregnene-11B,17a,21-triol-3,20-dione.

A mixture of 3 g. of the above compound, 100 cc. of t-butanol, 1 g. of selenium dioxide and a few drops of pyridine was refluxed under an atmosphere of nitrogen for 24 hours, filtered through celite, the filtrate was evaporated to dryness under reduced pressure and the residue was treated in acetone solution with decolorizing charcoal under reflux for 1 hour. 'The charcoal was removed by filtration, the acetone was evaporated and the residue purified by chromatography on neutral alumina, thus giving the 21-acetate of 16-met-hyl-9u-fluoro-1S-dehydro-hydrocortisone.

Oxidation of 1 g. of the latter compound with chromium trioxide in acetic acid, in accordance with the method described in Example 2, gave the 21-acetate'of 16-methyl-9u-fluoro-15-dehydro-cortisone, which was saponified with 1% methanolic potassium hydroxide, by applying the method described in Example 1, thus giving the free 16-methyl-9u-fluoro-lfi-dehydro-cortisone.

By following the esterification method of Example 3, the above compound was converted .into the 21-propionate of 16-methyl-9or-fluor0-15-dehydro-cortisone.

Example 6 5 g. of the 21-acetate of 16-methyl-9oa-fluoro-A -pregnene-l115,17a,21-triol-3,20-dione, prepared as described in the preceding example, was refluxed with 4 g. of selenium dioxide in mixture was 200 cc. of t-butanol and a few drops of pyridine, for 72 hours; the product was then isolated in accordance with the procedure reported in Example 1. There was thus obtained in only one step the 21-acetate of 16-rnethyl-9a-fiuoro-15-dehydro pred nisolone. Further treatment of the above compound with chloranil, in accordance with the method described in Example 1, gave the 2l-acetate of l6-rnethyl-9a-fluoro- 6,15-bis dehydro-prednisolone, which was treated with 1%. methanolic potassium hydroxide, by applying the method of Example 1, to produce the free 16-methyl-9u-fluoro- 6,15-bis-dehydro-prednisolone.

A solution of 1 g. of the above compound in 5 cc. of pyridine was treated with 3 cc. of cyclopentylpropionic anhydride, and kept overnight at room temperature. It was then poured into water, the formed precipitate Was filtered, washed with water, dried and recrystallized from acetone-ether to afford the 21-cyclopentylpropionate of 16-methyl-9a-fluoro-6,1S-bis-dehydroprednisolone.

Example 7 In accordance with the method described in Example 1, 2 g. of the 21-propionate of 16-methyl-9u-fluoro-15- dehydro-cortisone, prepared as described in Example 5, was refluxed With chloranil in mixture with ethyl acetate and acetic acid, to produce the 21-propionate of 16- n1ethyl-9u-fluoro-6,15-bis-dehydrocortisone.

Example 8 vIn accordance with the proceure described in Example 5, 10 g. of A -allopregnen-3fi-ol-11,20-dione-acetate, described by Djerassi et a1. in'J. Am. Chem. Soc. 74', 3634 (1952), were treated with an etheral solution of diazomethane, and the resulting pyrazoline, without further purification, was decomposed by the thermal treatment described by Wettstein et al. in Helv. Chem. Acta XXVll, 1803 (1944), by gradually heating to to C. in high vacuum. Recrystallization of the crudeproduct from acetone-ether gave 16-methyl-A -allopregnen-3B- ol-1l,20-dione-acetate, M.P. 163-65 C., [u] +26 (chloroform), A 248-50, 310-14 my, log 6 3.98, 2.09, in a 65% yield.

A solution of 5 g. of the above compound in 20 cc. of methylene chloride and 150 cc. of methanol was cooled to 0 C. and treated dropwise under stirring with 10 cc. of 10% aqueous sodium hydroxide solution and simultaneously with 30 cc. of 35% hydrogen peroxide, maintaining the temperature below 5 C. The reaction mixture was stirred for 1 hour further at 0 C. and then allowed to stand at room temperature for 4 days, poured into ice water and extracted with methylene chloride.

The combined extracts were washed with water to neu-' tral, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from acetone-ether aflorded 16/3 methyl 16oz, 17u oxido allopregnan-3B-ol-1L20- diolnle, M.P. 183-85", [a] +87.3 (chloroform), in 87% yie A solution of 5 g. of the preceding epoxide in 100 cc. of acetone was treated with aqueous hydrobromic acid solution, in accordance with the method described in Example 5. There was thus obtained '16-methyl-A allopregnene-3fi, 17o-diol-11,20-dione, in 92% yield, M.P. 25759 C. [0:1 65 (pyridine).

In accordance with the method described in Example 1, the latter compound was then monoiodinated at C-21 by reaction with iodine and calcium oxide in tetrahydrofurane-methanol and the resulting 2l-iodo derivative was treated with potassium acetate in acetone. Chromatography of the crude product gave the 21-acetate of 16- methyl 15 dehydro-allopregnene-3/3,17u-21-triol-11,20 dione, M.P. 18991, [oc] +13.6 (chloroform).

A solution of 3 g. of the above compound in 60 cc. of acetone was treated with an 8 N solution of chromic acid, following the procedure described in Example 1. There was thus obtained 16-methyl-A -allopregnene-17a- 21-diol-3,1 1,20-trione 21-monoacetate.

A stirred mixture of 1 g. of the above compound, 50 cc. of t-amyl alcohol, 300 mg. of selenium dioxide and 0.1 cc. of pyridine was refluxed for 24 hours under an atmosphere of nitrogen; 300 mg. more of selenium dioxide and 0.1 cc. of pyridine were added, and the reaction mixture refluxed for 24 hr. further. It was then cooled, filtered through celite and the filtrate evaporated to dryness under reduced pres-sure. The residue was triturated with Water and the precipitate was collected, washed with water and purified by chromatography on neutral alumina, the fractions eluted with benzenemethylene chloride 1:4 gave the pure 16-methyl15-dehydro-prednisone acetate, identical with that obtained in Example 2.

Example 9 By a conventional saponification with methanolic potassium hydroxide, 16-methyl-15-dehydrocortisone 21- acetate, obtained as described in Example 2, is converted to the free 16-methyl-1S-dehydro-cortisone.

Example 10 By conventional esterification with acetic anhydride and p-toluenesulfonic acid, 16-methyl-1S-dehydro-cortisome is converted to its 17,21-diacetate.

We claim:

1. A compound of the formula wherein R is selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid of up to 12 carbon atoms; X is selected from the group consisting of hydrogen and fluorine; Y is selected from the group consisting of CHnOR 16-methyl-lS-dehydro-cortisone. 16-methyl-15-dehydro-cortisone ZI-acetate. 16-methyl-1S-dehydro-cortisone 17,21-diacetate. 16-methyl-15-dehydrocortisone 21-propionate. 16-methyl-1Sdehydro-prednisolone.

10. l6-methyl-IS-dehydro-prednisolone ZI-acetate.

11. 16-methyl-1S-dehydro-prednisone 21-acetate.

12. 1fi-methyl-lS-dehydro-prednisone 21-propionate.

13. 16-methyl-9u-fluoro-IS-dehydro-hydrocortisone 21-acetate.

14. 16-methyl-9a-fluoro-IS-dehydro-cortisone.

15. 16-methyl-9a-fluoro-1S-dehydro-cortisone 21-acetate.

16. 16-rnethy1-9u-fluoro-1S-dehydro-cortisone 21-propionate.

17. 16-methyl-9a-fluoro-1S-dehydro-prednisolone 21- acetate.

18. 16-methyl-A -pregnadiene-17a,21-diol-3,20- dione.

19. 16-methyl-A -pregnacliene-17a,21-dio1-3,20-dione 21-acetate.

20. 1G-methyl-A allopregnene-3,9,17a,21-trio1-11,20- dione.

21. 16-methyl-A -allopregnene-170:,21-diol-3,l1,20- trione ZI-acetate.

e es a w 22. A compound of the formula CHzOR wherein R is selected from the group consisting of hydrogen and the acyl radical of a hydrocarbon carboxylic acid of up to 12 carbon atoms; X is selected from the group consisting of hydrogen and fluorine; Y is selected from the group consisting of and :0; and Z is the linkage between 0-1 and C-2 selected from the group consisting of single bond and double bond.

23. 16-methyl-6,15-bis-dehydro-prednisolone 21-acetate.

24. l6-methyl-6,1S-bis-dehydro-prednisone.

25. 16-methyl-6,15-bis-dehydro-prednisone 21-propionate.

26. 16-methyl-9a-fluoro-6,15-bis-dehydrocortisone 21- propionate.

27. 16-methyl-9a-fluoro-6,15-bisdehydroprednisolone.

28. 16-methyl-9a-fluoro-6,l5-bis-dehydro-prednisolone 21-acetate.

29. 16-methyl-9a-fluoro-6,15-bis-dehydro-prednisolone 2l-cyclopentyl-propionate.

30. A compound selected from the group consisting of:

omen

No references cited.

LEWIS GOTTS, Primary Examiner.

LESLIE H. GASTON, ELBERT L. ROBERTS,

M. L. WILLIAMS, Examiners. 

1. A COMPOUND OF THE FORMULA
 30. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF: 